NZ244078A - N-substituted aminomethanediphosphonic acid derivatives, and pharmaceutical compositions thereof - Google Patents
N-substituted aminomethanediphosphonic acid derivatives, and pharmaceutical compositions thereofInfo
- Publication number
- NZ244078A NZ244078A NZ244078A NZ24407892A NZ244078A NZ 244078 A NZ244078 A NZ 244078A NZ 244078 A NZ244078 A NZ 244078A NZ 24407892 A NZ24407892 A NZ 24407892A NZ 244078 A NZ244078 A NZ 244078A
- Authority
- NZ
- New Zealand
- Prior art keywords
- formula
- compound
- salt
- thio
- oxy
- Prior art date
Links
- -1 N-substituted aminomethanediphosphonic acid Chemical class 0.000 title claims abstract description 64
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 56
- 230000003913 calcium metabolism Effects 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 82
- 238000000034 method Methods 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 239000004480 active ingredient Substances 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 12
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 6
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- LSUZAOFHZJUPDQ-UHFFFAOYSA-N [(3-phenoxypropylamino)-phosphonomethyl]phosphonic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)NCCCOC1=CC=CC=C1 LSUZAOFHZJUPDQ-UHFFFAOYSA-N 0.000 claims description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 2
- 241001125671 Eretmochelys imbricata Species 0.000 claims 1
- 239000007853 buffer solution Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000011521 glass Substances 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 101100490437 Mus musculus Acvrl1 gene Proteins 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000007858 starting material Substances 0.000 description 13
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- 150000002148 esters Chemical group 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 5
- ICVPXOZTKDAJJZ-UHFFFAOYSA-N bis(diethoxyphosphoryl)methanamine Chemical compound CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC ICVPXOZTKDAJJZ-UHFFFAOYSA-N 0.000 description 5
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- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 4
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 208000037147 Hypercalcaemia Diseases 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- 150000003973 alkyl amines Chemical class 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 3
- 235000013539 calcium stearate Nutrition 0.000 description 3
- 239000008116 calcium stearate Substances 0.000 description 3
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- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
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- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 2
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 235000012419 Thalia geniculata Nutrition 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000016383 Zea mays subsp huehuetenangensis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 1
- 229910000323 aluminium silicate Inorganic materials 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 210000001188 articular cartilage Anatomy 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 208000016738 bone Paget disease Diseases 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 1
- RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 1
- KMPWYEUPVWOPIM-LSOMNZGLSA-N cinchonine Chemical compound C1=CC=C2C([C@@H]([C@H]3N4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-LSOMNZGLSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
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- 230000005494 condensation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 150000005690 diesters Chemical group 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 150000002194 fatty esters Chemical class 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005446 heptyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000009973 maize Nutrition 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- FOLUVYDWTUKZHB-UHFFFAOYSA-N n-(dimethoxymethyl)-n-methyl-3-phenoxypropan-1-amine Chemical compound COC(OC)N(C)CCCOC1=CC=CC=C1 FOLUVYDWTUKZHB-UHFFFAOYSA-N 0.000 description 1
- DLDHEZJFNPKHCW-UHFFFAOYSA-N n-methyl-2-phenylsulfanylethanamine Chemical compound CNCCSC1=CC=CC=C1 DLDHEZJFNPKHCW-UHFFFAOYSA-N 0.000 description 1
- SBOUHGZVYFYWMK-UHFFFAOYSA-N n-methyl-3-phenoxypropan-1-amine Chemical compound CNCCCOC1=CC=CC=C1 SBOUHGZVYFYWMK-UHFFFAOYSA-N 0.000 description 1
- SASNBVQSOZSTPD-UHFFFAOYSA-N n-methylphenethylamine Chemical compound CNCCC1=CC=CC=C1 SASNBVQSOZSTPD-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000030991 negative regulation of bone resorption Effects 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 201000001245 periodontitis Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Obesity (AREA)
- Pharmacology & Pharmacy (AREA)
- Hematology (AREA)
- Animal Behavior & Ethology (AREA)
- Diabetes (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Breeding Of Plants And Reproduction By Means Of Culturing (AREA)
- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
- Dental Preparations (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
N-substituted aminomethanediphosphonic acids of the formula I, <CHEM> wherein R1, X, alk1, R2 and n are as defined in the description, and salts thereof, have valuable pharmaceutical properties and are effective e.g. in the treatment of conditions which can be associated with disorders of the calcium metabolism. They are manufactured in a manner known per se.
Description
<div class="application article clearfix" id="description">
<p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number £44078 <br><br>
24 ' 078 <br><br>
Priority Date(s): <br><br>
Complete Specification Fi!.:d: ?-r? <br><br>
Class: f5?n 5>$. <br><br>
Publication Date: ..?.?.?!?P. <br><br>
P.O. Journal, Nc: ! ZK) <br><br>
NO DRAWINGS" <br><br>
I— ^3 Alls igg? <br><br>
^ ^ ^ <br><br>
Patents Form No. 5 <br><br>
NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION <br><br>
N-SUBSTITUTED AMINOMETHANEDIPHOSPHONIC ACIDS <br><br>
WE, CIBA-GEIGY AG, a Swiss corporation of Klybeckstrasse 141, 4002 Basle, SWITZERLAND <br><br>
hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: <br><br>
- 1 - <br><br>
(followed by page la) <br><br>
2440/g <br><br>
4-18769/A <br><br>
N-substituted aminomethanediphosphonic acids <br><br>
The invention relates to N-substituted aminomethanediphosphonic acids of the formula I <br><br>
p03h2 <br><br>
R,- X - alk1— N - (CH= N)~ CH (I) <br><br>
r2 po3h2 <br><br>
wherein Rj is an aromatic radical, X is oxy, thio, sulphinyl, sulphonyl or a covalent bond, alkj denotes a divalent aliphatic radical, R2 is hydrogen or a monovalent aliphatic radical, n is 1, or, in case that X is oxy, thio, sulphinyl or sulphonyl, n may also be 0, and to salts thereof, to a process for the preparation of the compounds according to the invention, to pharmaceutical formulations containing the latter and to their use as active compounds for medicaments. <br><br>
The aromatic radical is, for example, a monocyclic or bicyclic aryl radical, such as a phenyl, naphthyl or indanyl radical. <br><br>
The aryl radicals mentioned can be substituted, such as monosubstituted, disubstituted or trisubstituted, particularly monosubstituted or disubstituted, especially by lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxyl, trifluoromethyl and/or halogen. <br><br>
Examples of monovalent aliphatic radicals are lower alkyl or lower alkenyl radicals, while examples of divalent aliphatic radicals are lower alkylene radicals. <br><br>
Oxy is -0-, thio is -S-, sulphinyl is -SO- and sulphonyl is -S02-. <br><br>
In the preceding and following text lower radicals and compounds are to be understood as <br><br>
preferably up to and including 4, carbon atoms. <br><br>
Lower alkyl is, for example, C1-C7alkyl, preferably C1-C4alkyl, such as methyl, ethyl, propyl, isobutyl or butyl, but can also be e.g. isobutyl, secondary butyl, tertiary butyl or a pentyl, hexyl or heptyl group. In particular, lower alkyl is methyl. <br><br>
Lower alkenyl is, for example, C2-C4alkenyl, such as vinyl, allyl or but-2-enyl, but can also be a C5-C7alkenyl group, such as pentyl, hexenyl or heptenyl. <br><br>
Lower alkylene is, for example, C2-C6alkylene, such as 1,2-ethylene, 1,3-propylene, 1,4-butylene or 1,5-pentylene. <br><br>
Lower alkoxy is, for example, CrC7alkoxy, preferably C1-C4alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, but can also be e.g. isobutyloxy, secondary butyloxy, tertiary butyloxy or a pentyloxy, hexyloxy or heptyloxy group. <br><br>
Lower alkylenedioxy is, for example, methylenedioxy or ethylenedioxy. <br><br>
Halogen is, for example, bromine, preferably chlorine or fluorine, but may be also iodine. <br><br>
Examples of salts of compounds of the formula I are salts thereof with pharmaceutical^ acceptable bases, such as non-toxic metal salts derived from metals of groups la, lb, Ila and lib, for example alkali metal salts, in particular sodium or potassium salts, alkaline earth metal salts, in particular calcium or magnesium salts, copper, aluminium or zinc salts, and also ammonium salts containing ammonia or organic amines or quaternary ammonium bases, such as aliphatic amines which can be C-hydroxylated, in particular mono-, di- or tri-lower alkylamines, for example methylamine, ethylamine or diethylamine, mono-, di- or tri-(hydroxy-lower alkyl)-amines, such as ethanolamine, diethanolamine or triethanolamine, tris-(hydroxymethyl)-methylamine or 2-hydroxy-tertiary butylamine, or N-(hydroxy-lower alkyl)-N,N-di-lower alkylamines or N-(polyhydroxy-lower alkyl)-N-lower alkylamines, such as 2-(dimethylamino)-ethanol or D-glucamine, or quarternary aliphatic ammonium hydroxides, for example tetrabutylammonium hydroxide. Both complete and partial salts, i.e. salts containing 1,2, 3 or 4, preferably 2, equivalents of base per mole of acid of the formula I are embraced. <br><br>
The compounds of the formula I and their salts have valuable pharmacological properties. <br><br>
n t ? r> i <br><br>
/ •••'. . ? i V- <br><br>
-3- <br><br>
In particular they have a pronounced regulating action on the calcium metabolism of warm-blooded animals. Thus in rats they effect a pronounced inhibition of bone resorption which can be demonstrated both in the test set-up specified in Acta Endocrinol. 78, 613-24 (1975) and by means of the PTH-induced increase in the serum calcium level after subcutaneous administration in doses of about 0.01 to about 1.0 mg/kg, and in the TPTX-(thyroparathyroidectomised) rat model by means of the experimental hypercalcaemia initiated by vitamin D3 after the administration of doses of about 0.003 to about 0.05 mg/kg subcutaneously and, in part, also perorally. The tumour hypercalcaemia induced by Walker-256 tumours is also inhibited after peroral administration of about 1.0 to about 100 mg/kg. They also exhibit, in doses of about 0.01 to about 1.0 mg/kg subcutaneously a marked inhibition of the progress of chronic arthritic processes in adjuvant arthritis of rats in the test-set up of Newbold, Brit. J. Pharmacology 2J., 127 (1963) and of Kaibara et al., J. Exp. Med. 159, 1388-96 (1984). The indications of tumour-induced hypercalcaemia, bone metastases and Paget's disease are prominent in this respect. <br><br>
The compounds of the formula I and salts thereof are therefore excellently suitable for use as active compounds for medicaments for the treatment of diseases which can be associated with disturbances of calcium metabolism, for example inflammatory processes in joints, degenerative processes in articular cartilage, osteoporosis, periodontitis, hyperparathyroidism and calcium deposits in blood vessels or in prosthetic implants. <br><br>
The invention relates primarily to compounds of the formula I wherein Rt is a phenyl or naphthyl radical which radical is unsubstituted or mono-, di- or tri-substituted by substituents selected from lower alkyl, lower alkoxy, lower alkylcnedioxy, hydroxyl, <br><br>
halogen and trifluoromethyl, X is oxy, thio, sulphinyl, sulphonyl or a covalent bond, alkj is lower alkylene, R2 is hydrogen, lower alkyl or lower alkenyl, n is 1, or, in case that X is oxy, thio, sulphinyl or sulphonyl, n may also be 0, and salts thereof, in particular pharmaceutical^ acceptable salts thereof. <br><br>
In particular, the invention relates to compounds of the formula I wherein R! is a phenyl radical which is unsubstituted or mono- or disubstituted by substituents selected from CrC4alkyl, C1-C4alkoxy, CrC4alkylenedioxy, hydroxyl, halogen and trifluoromethyl, X is oxy, thio, sulphonyl or a covalent bond, alk1 is C2-C6alkylene, R2 is hydrogen or Cj-C4alkyl, n is 1, or, in case that X is oxy, thio or sulphonyl, n may also be 0, and to salts thereof, in particular pharmaccutically acceptable salts thereof. <br><br>
? a A n ? <br><br>
CL. k » - <br><br>
-4- <br><br>
The invention relates especially to compounds of the formula I wherein Rj is phenyl which is unsubstituted or substituted by CrC4alkyl, CrC4alkoxy, hydroxyl, halogen or trifluoromethyl, X is oxy, thio or a covalent bond, alkt is C2-C4alkylene, R2 is hydrogen or C^Qalkyl, n is 1, or, in case that X is oxy or thio, n may also be 0, and to salts thereof, in particular to pharmaceutical^' acceptable salts thereof. <br><br>
First and foremost, the invention relates to compounds of the formula I wherein Rj is phenyl which is unsubstituted or substituted by Cj-C4alkyl, CrC4alkoxy, hydroxyl or halogen, X is oxy or thio, allq is C2-C4alkylene, R2 is hydrogen or C1-C3alkyl, and n represents 1, and to salts thereof, in particular to phamiaceutically acceptable salts thereof. <br><br>
The invention relates especially to the compounds of the formula I mentioned in the examples and to salts thereof, in particular pharmaceutical^' acceptable salts thereof. <br><br>
The compounds of formula I can be prepared in a manner known per se, for example by a) in a compound of the formula II <br><br>
in which Rj, n, X, alkj, R2 and alk2 are as defined above, Xt is a functionally modified phosphono group and X2 is a free or functionally modified phosphono group, converting functionally modified phosphono Xt and, if appropriate, X2 into the free phosphono group, or b) for the manufacture of a compound of formula I having n = 1, reacting a compound of formula III <br><br>
R1-X-a!k1-N-CH=0 (ni) <br><br>
R2 <br><br>
24 4 07 <br><br>
-5- <br><br>
wherein Rx, X, alkj and R2 are as defined under formula I, or a functional derivative thereof, with a compound of formula IV, <br><br>
P03H2 <br><br>
H2N — CH (iv) <br><br>
po3h2 <br><br>
or a suitable salt thereof; or c) for the manufacture of a compound of formula I having n = 0, reacting a compound of formula Ilia <br><br>
R,—X-alk,—Y3 (nia) <br><br>
wherein Rt, X and alkj are as defined under formula I and Y3 is reactive esterified hydroxyl, with a compound of formula IVa p03h2 <br><br>
hn — ch (iva) <br><br>
r2 po3h2 <br><br>
wherein R2 is as defined under formula I, or a suitable salt thereof; and, if desired, converting a resulting compound into another compound of the formula I, separating a mixture of isomers obtainable in accordance with the process into the components and isolating the particular preferred isomer and/or converting a free compound obtainable in accordance with the process into a salt or converting a salt obtainable in accordance with the process into the corresponding free compound. <br><br>
The reactions according to the process and the preparation of novel starting materials or intermediates are effected analogously to the mode of reaction and formation of known starting materials and/or intermediates. The assistants customary in a particular case, such as catalysts, condensation agents and solvolysis agents and/or solvents or diluents and reaction conditions, such as temperature and pressure, and also, if appropriate, protective gases, arc used in this regard, even if not mentioned expressly below. <br><br>
A I f A <br><br>
; i / "» <br><br>
-6- <br><br>
Functionally modified phosphono groups to be converted into phosphono according to process variant a) are present, for example, in an ester form, in particular a diester form of the formula -P(=0)(0R)2 (Ila), in which OR is etherified hydroxyl, in particular lower alkoxy, lower alkanoyloxy-lower alkoxy or a phenoxy or a-phenyl-lower alkoxy group which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or hydroxyl, or is silyloxy, such as tri-lower alkylsilyloxy. <br><br>
The conversion of functionally modified phosphono groups into free phosphono groups is effected in a customary manner, such as by hydrolysis, for example in the presence of a mineral acid, such as hydrochloric or sulphuric acid, at about 80°C to about 110°C, for example at the boil, or, preferably, by reaction with a tri-lower alkyl halogenosilane, for example trimethylchlorosilane or especially trimethyliodosilane or trimethylbromosilane, preferably in methylene chloride within the temperature range from about 0°C to about 40°C, followed by treatment with water. When a compound of the formula II is reacted with a tri-lower alkyl halogenosilane, silylated intermediates of hitherto not exactly known structure are formed which which, when triturated with water or with aqueous alcohols, are converted into the diphosphonic acids of formula I. <br><br>
Compounds of the formula D which serve as starting materials for process variant a) can, for example, be prepared by condensing compounds of the formulae V and VI, <br><br>
I1 <br><br>
R^X-alk,-^ (V) and Y2—CH (VI) <br><br>
X2 <br><br>
in which one of the groups Yj and Y2 denotes a reactive esterified hydroxy group, such as halogen, especially chloro, bromo or iodo, or, in the case of Y1( a sulphonyloxy group, for example, a lower alkansulphonyloxy, especially methanesulphonyloxy, an optionally substituted benzenesulphonyloxy group, especially benezene-, p-bromobenzene- or p-toluenesulphonyloxy, or a sulphonyloxy group of the formula RpX-alki-O-SO^O-alkpX-Ri, and the other one represents a group of the formula -N(R2)-H (VII); or denotes a group of the formula -N(R2)-CH=0 (VIII), wherein the formyl group is preferably functionally modified, such as acetalised, for example, with a lower alkanol or a lower alkanediol, and Y2 is amino. <br><br>
Compounds of the formula V, wherein Y x is reactive esterified hydroxy or a group (VII), and compounds of the formula VI, wherein Y2 is halogen, amino or a group (VII) are known in the art. Compounds of the formula V, wherein Yi represents a group -N(R2)-CH=0 (VIE) can be manufactured, for example, by reacting a corresponding compound of the formula R1-X-alk1-NH2 (IX) with a N,N-disubstituted formamide, such as N,N-dimethyl formamide, or, preferably an acetal thereof, such as a N.N-dimethyl formamide di-lower alkyl or lower alkylene acetal, especially N.N-dimethyl formamide dimethyl acetal. <br><br>
Process (b): Preferably, a functional derivative of a compound of formula in is used. <br><br>
A functional derivative of a compound of formula III is preferably a di-lower alkyl acetal, especially dimethyl acetal. <br><br>
Optionally, the reaction is carried out in the presence of a condensating agent, e.g. P0C13. <br><br>
Process (c): Reactive esterified hydroxyl Y3 is defined in the same manner as Y, Yj and Y2 above and represents e.g. halogen. <br><br>
The conversion according to process (c) represents a well-known N-alkylation reaction via nucleophilic substitution. <br><br>
Processes (b) and (c) are similar to the manufacture of the compounds of formula n as described under process (a). <br><br>
Compounds obtainable in accordance with the process can be converted in a customary manner into other compounds of the formula I. <br><br>
Thus a monovalent aliphatic radical R2 can be introduced into compounds of the formula I in which R2 is hydrogen in a customary manner by reaction with a reactive ester of the formula R2-Y (X) in which Y is reactive esterified hydroxyl, for example a halogen atom, such as chlorine, bromine or iodine, or a sulphonyloxy group, for example methanesulphonyloxy or p-toluenesulphonyloxy, or by reaction with an aliphatic aldehyde or ketone of the formula R2=0 (Xa) under reducing conditions. The reaction with oxo compounds (Xa) is carried out, for example, in the presence of a reducing agent, for example, of an alkali metal borohydride, for example sodium cyanoborohydride, by <br><br>
O /. >* <br><br>
Jjf * . <br><br>
-8- <br><br>
catalytic hydrogenation or by treatment with formic acid. In a preferred embodiment a corresponding compound of the formula la can be substituted by a lower alkyl radical R2 under reducing conditions by means of a lower alkanal, for example formaldehyde, and formic acid. <br><br>
It is also possible to oxidize compounds of the formula I in which X is thio in a customary manner to give the corresponding compound of the formula I in which X is sulphinyl or sulphonyl, for example by treatment with an inorganic peroxy compound, for example hydrogen peroxide, persulphuric acid, or an organic peroxy compound, such as perbenzoic acid or m-chloroperbenzoic acid. <br><br>
It is also possible to introduce substituents into the radical Rt of compounds of the formula I, for example lower alkyl by reaction with a lower alkyl halide in the presence of aluminium trichloride, lower alkoxy, for example by nitration, reduction of the nitro group to give the amino group, diazotisation of the latter and treatment of the diazonium salt formed with the corresponding lower alkanol under hot conditions, and halogen, for example, by treatment with chlorine or bromine, advantageously in the presence of a Lewis acid, for example iron-Ill chloride. It is also possible, however, to replace halogen by trifluoromethyl, for example by treatment with trifluoroiodomcthane in the presence of copper powder or copper-I iodide. <br><br>
Depending on the choice of starting materials and procedures, the novel compounds can be present in the form of one of the possible isomers, for example, depending on the number of asymmetric carbon atoms, as optical isomers, such as in the form of an enantiomer, such as antipodes or diastereomers or mixtures thereof, such as mixtures of enantiomers, for example racemates, mixtures of diastereomers or mixtures of racemates. <br><br>
Resulting mixtures of diastereomers and mixtures of racemates can be separated into the pure diastereomers or racemates, respectively, in a known manner on the basis of the physico-chemical differences between the constituents, for example by chromatography and/or fractional crystallization. Resulting racemates can also be resolved into the optical antipodes by known methods, for example by recrystallisation from an optically active solvent, with the help of microorganisms by reacting a compound of the formula I with an optically active base or with an optically active alcohol and separating the resulting diastereomeric esters, for example on the basis of their different solubilities, into the diastereomers, from which the enantiomers can be liberated by the action of suitable <br><br>
r\ / f ^ <br><br>
£ S' 0 U / <br><br>
-9- <br><br>
agents. Racemates of the formula I can also be resolved, by reaction with an optically active base, into mixtures of the diastereomeric salts and separation of the latter into the diastereomers, from which the enantiomers can be liberated in the manner customary in each case. <br><br>
Examples of optically active bases which are customary for this purpose are optically active alkaloids, such as quinine, cinchonine, brucine and the like, or, in particular, a-phenylethylamine. <br><br>
It is also possible to convert resulting salt-forming compounds into salts in a manner known per se, for example by reacting a solution of the free solvent in a suitable solvent or solvent mixture with an appropriate base or with a suitable ion exchanger. <br><br>
Resulting salts can be converted into the free compounds in a manner known per se, for example by treatment with an acid, such as a mineral acid, for example hydrochloric acid. <br><br>
Resulting salts can be converted into other salts in a manner known per se, for example by treatment with a suitable base, such as sodium hydroxide or potassium hydroxide, <br><br>
ammonia or a suitable amine. <br><br>
The compounds of the formula I, including their salts, can also be obtained in the form of hydrates or can occlude the solvent used for crystallization. <br><br>
Because of the close relationship between the novel compounds in the free form and in the form of their salts, what is stated in the preceding and following text in respect of the free compounds or the salts thereof also applies by analogy to the corresponding salts and free compounds, respectively. <br><br>
The invention also relates to those embodiments of the process in which a compound obtainable as an intermediate at any stage of the process is used as the starting material and the remaining stages are carried out, or a starting material is used in the form of a salt, or, in particular, is formed under the conditions of the reaction. <br><br>
The novel starting materials, which have been specially developed for the preparation of the compounds according to the invention, in particular the choice of starting materials leading to the compounds of the formula I which have been characterized initially as <br><br>
o f / f <br><br>
J f 1 • " , <br><br>
-10- <br><br>
preferred, the processes for their preparation and their use as intermediates also form an object of the invention. <br><br>
The novel compounds of the formula I can, for example, be used in the form of pharmaceutical formulations containing a therapeutically effective amount of the active substance, if appropriate together with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients which are suitable e.g. for enteral, such as oral, parenteral or transdermal administration. Thus tablets or gelatin capsules containing the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol or cellulose, and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Tablets can also contain binders, for example magnesium aluminium silicate, starches, such as maize, wheat, rice or arrow root starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and, if desired, disintegrants, for example starches, agar, alginic acid or a salt thereof, for example sodium alginate, and/or effervescent mixtures, or absorbents, dyes, flavouring substances and sweeteners. The novel compounds of the formula I can also be used in the form of formulations capable of being administered parenterally or in the form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, it being possible to prepare the latter before use, for example in the case of lyophilised formulations containing the active ingredient on its own or together with an excipient, for example mannitol. The pharmaceutical formulations can be sterilized and/or contain adjuncts, for example preservatives, stabilizers, wetting agents and/or emulsificrs, solubilisers, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical formulations, which, if desired can contain further pharmacologically active substances, are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, solution or lyophilising processes, and contain from about 0.1 % to 100 %, in particular from about 1 % to about 50 % of the active ingredient, up to about 100 % in the case of lyophilisates. <br><br>
Products suitable for parenteral administration are primarily aqueous solutions of the active ingredient in a water-soluble form, for example in the form of a water-soluble, pharmaceutically acceptablc salt, and also suspensions of the active ingredient, such as oily injection suspensions, in which case suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty esters, for example ethyl oleate, and also triglycerides arc used, or aqueous injection suspensions containing substances which <br><br>
a a F r> *7 <br><br>
/ ^ i •' <br><br>
i *■ * <br><br>
-11- <br><br>
increase the viscosity, for example sodium carboxymethyl cellulose, sorbitol and/or dextran, and, if appropriate stabilizers. <br><br>
Suitable formulations for transdermal application include an effective amount of a compound of the invention with carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. Characteristically, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. <br><br>
The invention also relates to the use of compounds of the formula I for the treatment of diseases due to disturbances of calcium metabolism, preferably by the provision of pharmaceutical formulations. The dosage of the compound of the formula I according to the invention can depend on various factors such as the mode of application, species, age and/or individual condition. Single doses contain, for example, from about 0.01 to about 0.1 mg, preferably 0.02 to 0.08 mg, per kilogram of body weight in the case of parenteral administration and about 0.2 to about 2.5 mg, preferably 0.3 to 1.5 mg, per kilogram of body weight in the case of oral administration. The preferred single doses thus amount to about 0.5 to 5.0 mg in the case of parenteral administration and to about 10 to 100 mg in the case of oral administration. The doses to be administered daily in the case of oral administration are between about 0.25 and about 10 mg/kg and for warm-blooded animals having a body weight of about 70 kg, preferably between about 20 mg and about 500 mg. <br><br>
The following examples serve to illustrate the invention; temperatures are quoted in degrees Centigrade and pressures in mbar. <br><br>
Example 1: 3.5 g (0.0073 mol) of N-(3-phenoxypropyl)-N-mcthyl-formamidino-methanediphosphonic acid tetraethyl ester are dissolved in 30 ml of dichloromethane, and 4.7 ml (0.036 mol) of trimethylbromosilane are added. After 72 hours at room temperature, the solvent is removed under reduced pressure. The remaining oil is dissolved in warm 95% aqueous methanol. On cooling, N-(3-phenoxypropyl)-N-mcthyl-formamidinomethanediphosphonic acid of m.p. 211-212° (decomp.) is obtained. <br><br>
The starting material may be obtained as follows: <br><br>
9 />. h n 7 A <br><br>
k J - VJ <br><br>
-12- <br><br>
16.5 g (0.1 mol) of N-(3-phenoxypropyl)-N-methyl-amine and 15.0 ml (0.1 mol) of N,N-dimethylformamide dimethyl acetal are stirred at 120° for 18 hours. After distillation under reduced pressure, N-(3-phenyoxypropyl)-N-methyl-formamide dimethyl acetal of b.p. 64-67° (0.001 mbar) is obtained. <br><br>
2.43 g (0.008 mol) of aminomethylenediphosphonic acid tetraethyl ester and 1.91 g (0.008 mol) of N-(3-phenoxypropyl)-N-methyl-formamide dimethyl acetal are dissolved in 30 ml of tetrahydrofuran and stirred under reflux for 5 hours. After removal of the solvent under reduced pressure, raw N-(3-phenoxypropyl)-N-methyl-lormamidinomethanediphosphonic acid tetraethyl ester is obtained which may be used without further purification. <br><br>
Example 2: 4.0 g (0.008 mol) of N-(2-phenylthioethyl)-N-methyl-formamidinomethane-diphosphonic acid tetraethyl ester are dissolved in 30 ml of dichloromethane, and 5.2 ml (0.040 mol) of trimethylbromosilane are added. After 72 hours at room temperature, the solvent is removed under reduced pressure. The remaining oil is dissolved in warm 95% aqueous methanol. On cooling, N-(2-phenylthioethyl)-N-methyl-formamidinomethane-diphosphonic acid of m.p. 215-216° (decomp.) is obtained. <br><br>
The starting material may be obtained as follows: <br><br>
8.0 g (0.048 mol) of N-(2-phenylthioethyl)-N-methyl-amine and 7.0 ml (0.048 mol) of N,N-dimethylformamide dimethyl acetal are stirred at 120° for 18 hours. After distillation under reduced pressure, N-(2-phenylthioethyl)-N-methyl-formamide dimethyl acetal of b.p. 85-89° (0.001 mbar) is obtained. <br><br>
2.43 g (0.008 mol) of aminomethylenediphosphonic acid tetraethyl ester and 1.93 g (0.008 mol) of N-(2-phenylthioethyl)-N-methyl-formamide dimethyl acetal are dissolved in 30 ml of tetrahydrofuran and stirred under reflux for 5 hours. After removal of the solvent under reduced pressure, raw N-(2-phenylthioethyl)-N-methyl-formamidinomcthane-diphosphonic acid tetraethyl ester is obtained which may be used without further purification. <br><br>
Example 3: 2.9 g (0.0065 mol) of N-(2-phenylethyl)-N-methyl-formamidinomethane-diphosphonic acid tetraethyl ester are dissolved in 30 ml of dichloromethane, and 4.2 ml (0.0325 mol) of trimethylbromosilane are added. After 72 hours at room temperature, the <br><br>
9 A £ ? R <br><br>
Sam I U <br><br>
-13- <br><br>
solvent is removed under reduced pressure. The remaining oil is dissolved in warm 95% <br><br>
aqueous methanol. On cooling, N-(2-phenylethyl)-N-methyl-formamidinomethanediphos-phonic acid of m.p. 223-224° (decomp.) is obtained. <br><br>
The starting material may be obtained as follows: <br><br>
6.76 g (0.050 mol) N-(2-phenylethyl)-N-methyl-amine and 7.4 ml (0.050 mol) N,N-dimethyl-formamide dimethyl acetal are stined under reflux in a bath of 120° for 18 hours. After distillation under reduced pressure, N-(2-phenylethyl)-N-methyl-formamide dimethyl acetal of b.p. 52-54° (0.001 mbar) is obtained. <br><br>
3.03 g (0.01 mol) of aminomethylenediphosphonic acid tetraethyl ester and 2.1 g (0.01 mol) of N-(2-phenylethyl)-N-methyl-formamide dimethyl acetal are dissolved in 30 ml of tetrahydrofuran and stirred under reflux for 5 hours. After removal of the solvent under reduced pressure, raw N-(2-phenylethyl)-N-methyl-formamidinomethanediphosphonic acid tetraethyl ester is obtained which may be used without further purification. <br><br>
Example 4: 3.0 g (0.0068 mol) of N-(3-phenoxypropyl)aminomethanediphosphonic acid tetraethyl ester are dissolved in 20 ml of dichloromethane, and 4.4 ml (0.0343 mol) of trimethylbromosilane are added. After 72 hours at room temperature, the solvent is removed under reduced pressure. The remaining oil is dissolved in warm 95% aqueous methanol. On cooling, N-(3-phenoxypropyl)aminomethanediphosphonic acid of m.p. <br><br>
226-228° (decomp.) is obtained. <br><br>
The starting material may be obtained as follows: <br><br>
3.03 g (0.01 mol) of aminomethylenediphosphonic acid tetraethyl ester, 2.3 g (0.01 mol) of 3-phenoxypropylbromide and 1.4 g (0.01 mol) of potassium carbonate are dissolved in 50 ml of dioxane and stirred under reflux for 24"hours. The major part of the solvent is distilled off, and the residue is partitioned between water and ethyl acetate. The organic layer is separated, washed with water, dried over sodium sulphate and evaporated to dryness yielding raw N-(3-phenoxypropyl)aminomethanediphosphonic acid tetraethyl ester which may be used without further purification. <br><br>
Example 5: In an analogous manner as described in Examples 1 to 4, also the following compounds can be manufactured: <br><br>
O / f <br><br>
✓ /• ll ? <br><br>
£ "r <br><br>
A <br><br>
14- <br><br>
(a) N-[3-(4-chlorophenoxy)propyl]-N-methyl-formamidinomethanediphosphonic acid, m.p. 204-205°C; <br><br>
(b) N-[3-(4-methylphenoxy)propyl]-N-meihyl-formamidinomethanediphosphonic acid; <br><br>
and <br><br>
(c) N-[3-(4-methoxyphenoxy)propyl]-N-methyl-formamidinomethanediphosphonic acid. <br><br>
Example 6: 4.7 g (0.0084 mol) of N-[3-(4-chlorophenoxy)propyl]-N-methyl-formamidino-methanediphosphonic acid tetraethyl ester are dissolved in 30 ml of dichloromethane, and 5.5 ml (0.042 mol) of trimethylbromosilane are added. After 72 hours at room temperature, the solvent is removed under reduced pressure. The remaining oil is dissolved in warm 95 % aqueous methanol. On cooling, N-[3-(4-chlorophcnoxy)propyl]-N-methyl-formamidinomethanediphosphonic acid of m.p. 204-205°C (decomposition) is obtained. <br><br>
The starting material is prepared as follows: <br><br>
4.0 g (0.02 mol) of N-[3-(4-chlorophenoxy)propyl]-N-methyl-amine and 3.0 ml (0.02 mol) of N,N-dimethylformamide dimethyl acetal are stirred at 120°C for 18 hours. After distillation under reduccd pressure, N-[3-(4-chlorophenoxy)propylJ-N-methyl-formamide dimethyl acetal of b.p. 92°C (0.005 mbar) is obtained. <br><br>
2.54 g (0.0084 mol) of aminomethylenediphosphonic acid tetraethyl ester and 2.30 g (0.0084 mol) of N-[3-(4-chlorophenoxy)propyl]-N-methyl-formamide dimethyl acetal are dissolved in 30 ml of tetrahydrofuran and stirred under reflux for 5 hours. After removal of the solvent under reduced pressure, raw N-[3-(4-chlorophenoxy)propyl]-N-methyl-formamidinomethanediphosphonic acid tetraethyl ester is obtained which may be used without further purification. <br><br>
Example 7: Tablets each containing 50 mg of N-(3-phenoxypropyl)-N-methyl-form-amidinomethanediphosphonic acid or a salt thereof, for example the disodium salt, can be prepared as follows: <br><br>
Composition (10,000 tablets) <br><br>
? & ^ 1 <br><br>
-15- <br><br>
Active ingredient <br><br>
Lactose <br><br>
Potato starch <br><br>
Gelatin <br><br>
Talc <br><br>
500.0 g 500.0 g 325.0 g 8.0 g 60.0 g 10.0 g 20.0 g q.s. <br><br>
Magnesium stearate <br><br>
Silicon dioxide (finely divided) <br><br>
Ethanol <br><br>
The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve. After the granules have dried, the remainder of the potato starch, the magnesium stearate and the silicon dioxide are admixed and the mixture compressed to give tablets each weighing 145.0 mg and containing 50.0 mg of active ingredient, which can, if desired, be provided with breaking grooves to enable the dosage to be more finely adjusted. <br><br>
Example 8: Lacquered tablets each containing 100 mg of N-(3-phenoxypropyl)-N-methyl-formamidinomethanediphosphonic acid or a salt thereof, for example the disodium salt, can be prepared as follows: <br><br>
Composition (for 1,000 lacquered tablets) <br><br>
Active ingredient 100.0 g <br><br>
Lactose 100.0 g <br><br>
Maize starch 70.0 g <br><br>
Talc <br><br>
Calcium stearate Hydroxypropylosc Shellac Water <br><br>
Methylene chloride <br><br>
8.5 g 1-5 8 2.36 g 0.64 g q.s. q.s. <br><br>
The active ingredient, the lactose and 40 g of the maize starch are mixed, moistened with a paste prepared (by heating) from 15 g of maize starch and water and granulated. The granules are dried and the remainder of the maize starch, the talc and the calcium stearate <br><br>
24 4 07 8 <br><br>
-16- <br><br>
are added and mixed with the granules. The mixture is compressed to give tablets (weight: 280 mg), and these tablets are lacquered with a solution of the hydroxypropylmethyl cellulose and the shellac in methylene chloride; final weight of the lacquered tablet: 283 mg. <br><br>
Example 9: Hard gelatin capsules each containing 100 mg of active ingredient, for example N-(3-phenoxypropyl)-N-methyl-formamidinomethanediphosphonic acid or a salt thereof, for example the disodium salt, can, for example, be prepared in the following way: <br><br>
Composition (for 1,000 capsules) <br><br>
Active ingredient 100.0 g <br><br>
Microcrystalline cellulose 30.0 g <br><br>
Sodium laurylsulphate 2.0 g <br><br>
Magnesium stearate 8.0 g <br><br>
Using a sieve of mesh width 0.2 mm, the sodium laurylsulphate is sieved onto the lyophilised active ingredient The two components arc intimately mixed. The microcrystalline cellulose is then sieved onto the mixture through a sieve of mesh width 0.9 mm. The mixture is again intimately mixed for 10 minutes. Finally, the magnesium stearate is sieved on using a sieve of mesh width 0.8 mm. After being mixed for a further 3 minutes, 390 mg of the resulting formulation are filled into each hard gelatin capsule of size 0. <br><br>
Example 10: A 0.2 % injection or infusion solution of N-(3-phcnoxypropyl)-N-methyl-formamidinomethanediphosphonic acid or one of its salts, for example its disodium salt, can, for example, be prepared in the following way: <br><br>
Composition (for 1,000 ampoules) <br><br>
Active ingredient 5.0 g <br><br>
Sodium chloride 22.5 g <br><br>
Phosphate buffer pH 7.4 300.0 g <br><br>
De-ionised water ad 2500.0 ml <br><br></p>
</div>
Claims (16)
1. An N-substituted aminomethanediphosphonic acid of the formula I<br><br> P03H2<br><br> R,— X-alk,<br><br> N- (CH=N)—CH<br><br> . n i<br><br> (I)<br><br> R,<br><br> P03H2<br><br> in which Rj is an aromatic radical, X is oxy, thio, sulphinyl, sulphonyl or a covalent bond,<br><br> alkj denotes a divalent aliphatic radical, R2 is hydrogen or a monovalent aliphatic radical, and n is 1, or, in case that X is oxy, thio, sulphinyl or sulphonyl, n may also be 0, or a salt thereof.<br><br>
2 . A compound as claimed in claim 1 of the formula I wherein is a phenyl or naphthyl radical which radical is unsubstituted or mono-, di- or tri-substituted by substituents selected from lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxyl, halogen and trifluoromethyl, with the proviso that phenyl cannot be tri-substituted by lower alkylenedioxy, X is oxy, thio, sulphinyl, sulphonyl or a covalent bond, alk^ is lower alkylene, Rj is hydrogen, lower alkyl or lower alkenyl, and n is 1, or, in case that X is oxy, thio, sulphinyl or sulphonyl, n may also be 0, or a salt thereof.<br><br>
3. A compound as claimed in claim 1 of the formula I wherein R! is a phenyl radical which is unsubstituted or mono- or disubstituted by substituents selected from CrC4alkyl, CrC4alkoxy, CrC4alkylenedioxy, hydroxyl, halogen and trifluoromethyl, X is oxy, thio, sulphonyl or a covalent bond, alkx is C2-C6alkylene, R2 is hydrogen or CrC4alkyl, and n is l, or, in case that X is oxy, thio or sulphonyl, n may also be 0, or a salt thereof.<br><br>
4. A compound as claimed in claim 1 of the formula I wherein Rj is phenyl which is unsubstituted or substituted by CrC4alkyl, CpQalkoxy, hydroxyl, halogen or trifluoromethyl, X is oxy, thio or a covalent bond, alkt is C2-C4alkylene, R2 is hydrogen or Ci-C4alkyl, and n is 1, or, in case that X is oxy or thio, n may also be 0, or a salt thereof.<br><br>
5. A compound as claimed in claim 1 of the formula I wherein Rt is phenyl which is<br><br> Mr \ ^<br><br> unsubstituted or substituted by CpQ^alkyl, C^Qalkoxy, hydroxyl or halogen, X is oxy ovf* *<br><br> thio, alk, is C2-C4alkylene, R2 is hydrogen or C1-C3alkyl, and n represents 1, or a salt | H<br><br> #E(<br><br> -19-<br><br> 24 4 V / ><br><br> thereof.<br><br>
6. N-(3-phenoxypropyl)-N-methyl-formamidinomethanediphosphonic acid according to claim 1 or a pharmaceutically acceptable salt thereof.<br><br>
7. N-(2-phenylthioethyl)-N-methyl-formamidinomethanediphosphonic acid according to claim 1 or a pharmaceutically acceptable salt thereof.<br><br>
8. N-(2-phenylethyl)-N-methyl-formamidinomethanediphosphonic acid according to claim 1 or a pharmaceutically acceptable salt thereof.<br><br>
9. N-(3-phenoxypropyl)aminomethanediphosphonic acid according to claim 1 or a pharmaceutically acceptable salt thereof.<br><br>
10. N-[3-(4-chlorophenoxy)propyl]-N-methyl-formamidinomethanediphosphonic acid according to claim 1 or a pharmaceutically acceptable salt thereof.<br><br>
11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and at least one pharmaceutically acceptable carrier.<br><br>
12. A compound according to any one of claims 1 to 10 for use in a method for the therapeutic treatment of the animal or human body.<br><br>
13. A compound according to any one of claims 1 to 10 for use in the treatment of conditions which can be associated with disorders of the calcium metabolism.<br><br>
14. The use of a compound according to any one of claims 1 to 10 in the manufacture of pharmaceutical compositions.<br><br>
15. The use of a compound according to any one of claims 1 to 10 in' the manufacture of pharmaceutical compositions for the treatment of conditions which can be associated with disorders of the calcium metabolism.<br><br>
16. A process for the manufacture of a compound of formula I according to claim I, or a salt thereof, which comprises<br><br> 244078<br><br> -20-<br><br> a) in a compound of the formula II<br><br> in which Rt, n, X, alkj and are as defined for formula I, is a functionally modified phosphono group and X2 is a free or functionally modified phosphono group, converting functionally modified phosphono X: and, if appropriate, X2 into the free phosphono group,<br><br> or b) for the manufacture of a compound of formula I having n = 1, reacting a compound of formula III<br><br> R,— X- alk,— N-CH=0 (ni)<br><br> R2<br><br> wherein Rlt X, alkj and R2 are as defined for formula I, or a functional derivative thereof, with a compound of formula IV,<br><br> P03H2<br><br> H2N— CH (IV) '<br><br> P03H2<br><br> or a suitable salt thereof; or c) for the manufacture of a compound of formula I having n = 0, reacting a compound of formula ma<br><br> R,—X-alk,—Y3 (Ilia)<br><br> wherein Rt, X and alkj are as defined for formula I and Y3 is reactive esterified hydroxyl, with a compound of formula IVa<br><br> 244078<br><br> -21-<br><br> hn ch<br><br> (IVa)<br><br> r2 po3h2<br><br> wherein R2 is as defined for formula I, or a suitable salt thereof; and, if desired,<br><br> converting a resulting compound into another compound of the formula I, separating a mixture of isomers prepared in accordance with the process into the individual iscmers and isolating the particular preferred isomer and/or converting a free compound prepared in accordance with the process into a salt or converting a salt prepared in accordance with the process into the corresponding free compound.<br><br> c\b4gbjgy ag ^<br><br> BYTHEI^nTO RNEYS baldwin, son & carey<br><br> </p> </div>
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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EP91810682 | 1991-08-27 |
Publications (1)
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NZ244078A true NZ244078A (en) | 1994-12-22 |
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Application Number | Title | Priority Date | Filing Date |
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NZ244078A NZ244078A (en) | 1991-08-27 | 1992-08-25 | N-substituted aminomethanediphosphonic acid derivatives, and pharmaceutical compositions thereof |
Country Status (19)
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US (1) | US5281748A (en) |
EP (1) | EP0531253B1 (en) |
JP (1) | JPH05222074A (en) |
KR (1) | KR930004317A (en) |
AT (1) | ATE147396T1 (en) |
AU (1) | AU657983B2 (en) |
CA (1) | CA2076801A1 (en) |
DE (1) | DE69216514T2 (en) |
DK (1) | DK0531253T3 (en) |
ES (1) | ES2096061T3 (en) |
FI (1) | FI923797A (en) |
GR (1) | GR3022243T3 (en) |
HU (1) | HUT62303A (en) |
IL (1) | IL102959A (en) |
MX (1) | MX9204905A (en) |
NO (1) | NO923331L (en) |
NZ (1) | NZ244078A (en) |
TW (1) | TW207543B (en) |
ZA (1) | ZA926434B (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0541037A3 (en) * | 1991-11-06 | 1997-02-26 | Takeda Chemical Industries Ltd | Squalene synthetase inhibitory composition and use thereof |
TW258729B (en) * | 1992-06-22 | 1995-10-01 | Ciba Geigy | |
DE4223940A1 (en) * | 1992-07-21 | 1994-01-27 | Boehringer Mannheim Gmbh | New acyclic diphosphonic acid derivatives containing amidine groups, processes for their preparation and medicaments containing these compounds |
GB9300641D0 (en) * | 1993-01-14 | 1993-03-03 | Zeneca Ltd | Process |
DE19719680A1 (en) | 1997-05-09 | 1998-11-19 | Boehringer Mannheim Gmbh | Use of diphosphonic acids for the preventive treatment of long-term consequences of bladder enlargement or replacement |
IT1303672B1 (en) | 1998-07-28 | 2001-02-23 | Nicox Sa | NITRATED SALTS OF DRUGS ACTIVE IN BONE DISORDERS |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
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DE2316396C3 (en) * | 1973-04-02 | 1975-09-18 | Joh. A. Benckiser Gmbh, 6700 Ludwigshafen | N (1,1-di-phosphono-ethyl) acetamidine, its production and use for stone prevention |
DE3208600A1 (en) * | 1982-03-10 | 1983-09-22 | Henkel KGaA, 4000 Düsseldorf | AMIDINODIPHOSPHONIC ACIDS |
US4761406A (en) * | 1985-06-06 | 1988-08-02 | The Procter & Gamble Company | Regimen for treating osteoporosis |
DE3623397A1 (en) * | 1986-07-11 | 1988-01-14 | Boehringer Mannheim Gmbh | NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
US4963681A (en) * | 1987-07-06 | 1990-10-16 | Norwich Eaton Pharmaceuticals, Inc. | Process for synthesis of aminomethylene phosphonoalkylphosphinates |
PH26923A (en) * | 1989-03-08 | 1992-12-03 | Ciba Geigy | N-substituted amino alkanediphosphonic acids |
IE912115A1 (en) * | 1990-06-25 | 1992-01-01 | Takeda Chemical Industries Ltd | Bisphosphonic acid derivatives, their production and use |
US5043099A (en) * | 1990-07-13 | 1991-08-27 | Kreh Robert P | Mono- and di-substituted (diphosphonoalkylamino methyl)-4-hydroxybenzenesulfonic acid |
ATE133677T1 (en) * | 1990-12-19 | 1996-02-15 | Takeda Chemical Industries Ltd | BISPHOSPHONIC ACID DERIVATIVES, THEIR PRODUCTION AND THEIR USE |
-
1992
- 1992-08-18 DK DK92810629.3T patent/DK0531253T3/en active
- 1992-08-18 AT AT92810629T patent/ATE147396T1/en active
- 1992-08-18 EP EP92810629A patent/EP0531253B1/en not_active Expired - Lifetime
- 1992-08-18 TW TW081106522A patent/TW207543B/zh active
- 1992-08-18 ES ES92810629T patent/ES2096061T3/en not_active Expired - Lifetime
- 1992-08-18 DE DE69216514T patent/DE69216514T2/en not_active Expired - Fee Related
- 1992-08-21 US US07/936,982 patent/US5281748A/en not_active Expired - Fee Related
- 1992-08-24 FI FI923797A patent/FI923797A/en not_active Application Discontinuation
- 1992-08-25 JP JP4225966A patent/JPH05222074A/en active Pending
- 1992-08-25 NZ NZ244078A patent/NZ244078A/en unknown
- 1992-08-25 MX MX9204905A patent/MX9204905A/en unknown
- 1992-08-25 CA CA002076801A patent/CA2076801A1/en not_active Abandoned
- 1992-08-25 AU AU21288/92A patent/AU657983B2/en not_active Ceased
- 1992-08-26 IL IL102959A patent/IL102959A/en not_active IP Right Cessation
- 1992-08-26 KR KR1019920015404A patent/KR930004317A/en not_active Application Discontinuation
- 1992-08-26 HU HU9202754A patent/HUT62303A/en unknown
- 1992-08-26 NO NO92923331A patent/NO923331L/en unknown
- 1992-08-26 ZA ZA926434A patent/ZA926434B/en unknown
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1997
- 1997-01-09 GR GR960403659T patent/GR3022243T3/en unknown
Also Published As
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ZA926434B (en) | 1993-04-28 |
FI923797A0 (en) | 1992-08-24 |
DK0531253T3 (en) | 1997-01-27 |
NO923331L (en) | 1993-03-01 |
MX9204905A (en) | 1993-04-01 |
HUT62303A (en) | 1993-04-28 |
EP0531253B1 (en) | 1997-01-08 |
IL102959A (en) | 1998-01-04 |
ATE147396T1 (en) | 1997-01-15 |
DE69216514T2 (en) | 1997-07-31 |
CA2076801A1 (en) | 1993-02-28 |
DE69216514D1 (en) | 1997-02-20 |
GR3022243T3 (en) | 1997-04-30 |
AU657983B2 (en) | 1995-03-30 |
NO923331D0 (en) | 1992-08-26 |
US5281748A (en) | 1994-01-25 |
EP0531253A1 (en) | 1993-03-10 |
ES2096061T3 (en) | 1997-03-01 |
JPH05222074A (en) | 1993-08-31 |
IL102959A0 (en) | 1993-01-31 |
FI923797A (en) | 1993-02-28 |
KR930004317A (en) | 1993-03-22 |
TW207543B (en) | 1993-06-11 |
HU9202754D0 (en) | 1992-12-28 |
AU2128892A (en) | 1993-03-04 |
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